Drug Interactions between capecitabine and esomeprazole

MONITOR: Coadministration of proton pump inhibitors (PPIs) has been reported to reduce the antitumor efficacy of capecitabine, although available data are inconsistent and conflicting. Several retrospective studies and post-hoc analyses of randomized controlled trials have demonstrated an adverse impact of PPI use on disease progression, recurrence rates, and/or survival outcomes in patients receiving capecitabine-containing chemotherapy for the treatment of gastroesophageal and colorectal cancers. A reduction in dissolution and subsequent absorption of capecitabine due to PPI-induced elevations in gastric pH has been proposed as the underlying mechanism of interaction. However, three pharmacokinetic studies conducted with antacid (Maalox) and PPIs (esomeprazole, rabeprazole) failed to show significant effects on plasma concentrations of capecitabine and its metabolites. Additionally, the association between PPIs and poorer oncologic outcomes was not seen with concomitant use of other acid-suppressing agents such as H2-receptor antagonists in a retrospective post hoc analysis of data from six completed colorectal cancer clinical trials. Subgroup analyses in this investigation also did not find a significant negative association with survival for concomitant PPI use across 980 patients receiving capecitabine and oxaliplatin (CapOx) with or without bevacizumab. Meanwhile, one retrospective study reported positive effects of omeprazole on response rate and disease-free survival in advanced rectal cancer treated with CapOx chemoradiotherapy (CRT) for two cycles prior to surgery. In vitro data have shown that PPIs may possess direct antitumor effects and can also re-sensitize drug-resistant colon adenocarcinoma cell lines to cytotoxic drugs by inhibiting a membranous proton pump known as vacuolar-ATPase (V-ATPase), which is overexpressed in resistant cancer cells. It is possible that suppressing the activity of V-ATPases helps to modulate the abnormal pH gradients in tumor microenvironment associated with tumorigenesis, tumor progression, and drug resistance. More recently, some investigators have conducted systematic reviews and meta-analyses that have cast doubt on the occurrence of a significant interaction between PPIs and capecitabine based on existing clinical, pharmacokinetic, and in vitro evidence. It is also unclear whether the potential negative effects of PPI use reported during capecitabine treatment in gastroesophageal and colorectal cancers may occur in other cancers.

MANAGEMENT: Based on available data, it may be advisable to avoid PPI use during treatment with capecitabine when possible. Alternative acid suppressing agents such as antacids and H2-receptor antagonists may be preferable in some cases. If PPIs are required, patients should be monitored and evaluated at regular intervals to ascertain the continued need for their use.

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